Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochon...

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Vydáno v:	eLife Ročník 9
Hlavní autoři:	Chiao, Ying Ann, Zhang, Huiliang, Sweetwyne, Mariya, Whitson, Jeremy, Ting, Ying Sonia, Basisty, Nathan, Pino, Lindsay K, Quarles, Ellen, Nguyen, Ngoc-Han, Campbell, Matthew D, Zhang, Tong, Gaffrey, Matthew J, Merrihew, Gennifer, Wang, Lu, Yue, Yongping, Duan, Dongsheng, Granzier, Henk L, Szeto, Hazel H, Qian, Wei-Jun, Marcinek, David, MacCoss, Michael J, Rabinovitch, Peter
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England eLife Sciences Publications Ltd 10.07.2020 eLife Sciences Publications, Ltd
Témata:	Age Aging Aging - drug effects Animals BASIC BIOLOGICAL SCIENCES Cardiac function Cardiomyocytes Catalase Connectin diastolic dysfunction Energy Metabolism Female Fitness equipment Heart Diseases - drug therapy Heart Diseases - physiopathology Human Biology and Medicine Male Mice Mice, Inbred C57BL Mitochondria Mitochondria - physiology Mitochondrial DNA Oligopeptides - administration & dosage Oxidation-Reduction Oxidative Stress Phenotypes Phosphorylation Redox properties Rodents Running human biology mouse mitochondria diastolic dysfunction cardiac function medicine aging oxidative stress
ISSN:	2050-084X, 2050-084X
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Shrnutí:	Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets for cardiac aging.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 USDOE AC05-76RL01830 PNNL-SA-150324 Deceased.
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.55513